A total of 1,103 patients participated in the multicenter, double-blind, randomized trial.

The study's most important finding was a negative one -- that pentoxifylline had no influence on mortality, Thursz told MedPage Today. "As suspected by many people, it has no role in the treatment of [alcoholic hepatitis]," he added.

Potential Short-Term Prednisolone Benefit

But there could be a short-term survival benefit with prednisolone alone, wrote the authors.

The 28-day survival rate was reduced in patients who received prednisolone, either with or without pentoxifylline, compared with those who did not (odds ratio 0.72, 95% CI 0.52 to 1.01; P=0.06).

"The findings suggest that the administration of 40 mg of prednisolone daily for 1 month may have a beneficial effect on short-term mortality but not on the medium-term or long-term outcome of alcoholic hepatitis," authors wrote.

But physicians must be cautious when using steroids given the risk of infection, Thursz said. Nearly twice as many patients who received prednisolone developed an infection compared with those who did not receive the steroid (13% and 7%, respectively; P=0.002).

One option to minimize infection risk would be to select patients who respond to treatment by looking at the change in serum bilirubin levels in the first week, Thursz added.

Still, the prednisolone results were somewhat disappointing for Jonathan Fenkel, MD, a gastroenterologist and director of the Jefferson Hepatitis C Center at Thomas Jefferson University Hospital in Philadelphia.

"For many years, we've been using prednisolone in patients, and in personal experience it works for some patients," he said. "I'm surprised that [prednisolone] did not show a more beneficial effect in this population of patients with severe alcoholic hepatitis."

Improvements in Supportive Care

Fenkel noted that the mortality rate in the placebo-placebo group (17%) was lower than in previous studies, which could have hindered the ability to show a difference in survival.

Thursz added that over the last several decades, the hepatology community improved its supportive care of this patient population. Patients are less frequently malnourished, have better access to intensive care units, receive renal replacement therapy, and are treated more aggressively for infections.

But mortality rates are still very high, Thursz warned. A total of 16% of patients had died by 28 days, 29% had died or undergone liver transplantation by 90 days, and 56% had died or undergone liver transplantation by 1 year.

Long-term mortality in the study was strongly influenced by the ability of patients to abstain from alcohol, Thursz said. "We very much need to concentrate on further research to reduce that mortality. Steroids are not the answer," he said.

"We need to strengthen hospital systems in order to help people get off their alcohol to address their addiction problems," he added.

Fenkel agreed. "This is a very difficult disease to treat," he added. "I think patients have a hard time understanding that if they're hospitalized for alcohol-related liver disease, they may not be here next year."

Study Details

Inclusion criteria were relatively broad to reflect real-world practice, Thursz said. Participants were 18 years or older, had a clinical diagnosis of alcoholic hepatitis, consumed more than 60 or 80 grams of alcohol per day (for women and men, respectively), had a serum bilirubin level greater than 80 mcmol per liter, and had a discriminant function of 32 or higher.

Exclusion criteria were jaundice for more than 3 months, cessation of alcohol consumption for more than 2 months before randomization, the presence of other causes of liver disease, and a serum aspartate aminotransferase level greater than 500 IU per liter or serum alanine transaminase level greater than 300 IU per liter.

Patients were assigned to one of four groups, including a placebo-placebo group, a prednisolone-placebo group, a pentoxifylline-placebo group, and a prednisolone-pentoxifylline group.

The primary endpoint was mortality at 28 days. Secondary endpoints were mortality or liver transplantation at 90 days and at 1 year.

Prednisolone dosing was 40 mg daily and pentoxifylline dosing was 400 mg three times daily.

The odds ratio for 28-day mortality among patients who received pentoxifylline, either with prednisolone or without, compared with patients who did not was 1.07 (95% CI 0.77 to 1.49, P=0.69).

Neither prednisolone nor pentoxifylline influenced mortality or the need for liver transplantation at 90 days or 1 year.

One study limitation was a younger patient population with greater rates of encephalopathy compared with recent trials, both factors which influence mortality, authors wrote.

Other limitations were that the diagnosis of alcoholic hepatitis was not confirmed by biopsy and that alcohol consumption was self-reported, authors added.

The study was funded by the National Institute for Health Research (NIHR) Health Technology Assessment program.

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